Ecnoglutide

2025年2月5号，诺德诺德发布2024年年报，其中司美格鲁肽注射液Ozempic®全球销售额为1203.42亿丹麦克朗（约合168.96亿美金），口服司美格鲁肽Rybelsus®全球销售额为233.01亿丹麦克朗（约合32.71亿美金），减肥版司美格鲁肽Wegovy®全球销售额为582.06亿丹麦克朗（约合81.72亿美金），以上三款产品2024年全球销售额共计2018.49亿丹麦克朗，约合283.39亿美金，而诺德诺德2024年全年销售额为2904.03亿丹麦克朗（约合407.73亿美金），司美格鲁肽的占比高达69.5%。毫无疑问，司美格鲁肽已经成为诺和诺德最炙手可热的一款产品，而这距离Ozempic® 2017年首次获批上市也才过去了仅仅7年。然而在产品生命周期越来越短的今天，司美格鲁肽还能再大卖几年？司美格鲁肽在国内外又面临着哪些挑战？下面我们将详细叙述 来自专利悬崖的挑战 众所周知，一款热卖的产品一旦失去专利的保护，其市场必然会受到仿制药的强烈冲击。前任“药王”修美乐（Humira）就是非常经典的例子。在专利到期前的5年时间内，修美乐的年销售额一直稳定在200亿美金上下，随着2022年底专利到期，2023年包括Amgen、Sandoz以及Samsung等10款仿制药全部涌入美国市场，而美国又是修美乐的主要市场，根据Abbvie的年报我们可以看到，由于受到仿制药的冲击，修美乐2023年与2024年销售额分别降到了144亿美金与89.93亿美金。照此趋势推测，2025年修美乐的销售数据将更加惨淡。 目前司美格鲁肽三款产品虽然都处于专利保护期内，但根据诺和诺德年报可以看到，其中国专利最早将于2026年到期，而2024年司美格鲁肽三款产品在中国的销售额为64.69亿丹麦克朗，约合66亿人民币，如此一大块“蛋糕”必然会引起国内药企的争夺。根据我国药监局CDE公布的数据，国内目前已经有6家药企对司美格鲁肽原料药进行了备案登记，分别为苏州天马医药、江苏诺泰澳赛诺、湖北健翔生物、浙江湃肽生物、海南中和药业以及齐鲁制药。除此之外也有多家公司宣布在司美格鲁肽原料药的生产过程取得重大进展。如北京铭研医药近日宣布通过对司美格鲁肽传统工艺技术进行创新性改进，成功实现百公斤级合成产能；丽珠集团在2024年的公告中提及，其新北江制药的司美格鲁肽原料药生产线已建成，具备年产原料药300公斤的生产能力；美药星制药公告称将投资2000万元，建成年产达600kg司美格鲁肽原料药生产线等。 除了原料药之外，国内在司美格鲁肽制剂方面更是硝烟弥漫。截止撰稿日期，国内已有4家企业向CDE提交了司美格鲁肽注射液的上市申请，分别是九源基因、丽珠集团、齐鲁制药以及珠海联邦。申报路径方面，九源基因、丽珠集团、珠海联邦均按照3.3类生物类似药申报，齐鲁制药则按2.2类化药申报。其中九源基因于2024年4月2号递交了司美格鲁肽注射液的上市申请并获受理，为国内首家，但遗憾的是，根据2024年12月31日药品通知件送达信息显示，九源基因的司美格鲁肽注射液未获批准上市。但需要注意的是，这次未获批的只是九源基因申报的6个规格中的其中两个，另外4个规格仍在正常的审评审批中。而除了上述4家企业，目前也有多家药企的司美格鲁肽注射液处于临床阶段，包括太极集团、海南中和药业、山东新时代、中山万汉制药等。可以预想，等到2026年司美格鲁肽在国内专利到期，将会有大量仿制药上市，分割其国内市场份额。 来自其他多肽的挑战 目前，司美格鲁肽注射液在全球最大的竞争对手毫无疑问是礼来的替尔泊肽。该化合物的两款产品Mounjaro与Zepbound分别于2022年5月与2023年11月获美国FDA批准上市，虽然这两款产品的上市时间较短，但根据礼来发布的2024年年报可以看到，Mounjaro全年销售额为115.40亿美金，与去年相比上涨124%；Zepbound全年销售额为49.25亿美金，两款产品的合计年销售额已达164.65亿美金。同时，为了降低自费患者每月的用药费用，礼来公司于2025年2月25号宣布推出7.5mg与10mg Zepbound单剂量西林瓶包装，而早在2024年8月礼来就推出了2.5mg与5mg Zepbound单剂量西林瓶包装，如此一来，2.5mg规格的Zepbound每月花费可降低至349美金，而10mg规格每月也仅需699美金。如此低价优惠，外加上更为强大的减肥效果，未来毫无疑问会进一步渗透司美格鲁肽注射液的市场份额。 司美格鲁肽注射液在国内同样面临着各种挑战，2025年1月26号，国家药监局发布公告称，批准上海银诺医药申报的依苏帕格鲁肽α注射液（商品名：怡诺轻）上市，用于成人2型糖尿病患者的血糖控制。2月11日，依苏帕格鲁肽α开出了全国首张处方。依苏帕格鲁肽α是国内首个拥有自主知识产权的人源超长效GLP-1受体激动剂，其半衰期长达204小时，是目前全球已上市GLP-1药物中半衰期最长的产品，药频次为每周一次，甚至有望实现每两周给药一次。从国内某大型零售平台可以看到，其1mg/0.5ml与3mg/0.5ml规格每盒（2支装）价格分别在540与1400人民币左右，每个月花费分别在1080与2800人民币。 除了银诺的依苏帕格鲁肽α注射液，国内也有多款自主研发的产品进入申报上市以及后临床阶段，如先为达生物的伊诺格鲁肽（Ecnoglutide ，XW003），已于2024年12月17日向CDE递交了新药上市申请。伊诺格鲁肽注射液是一种具有cAMP偏向性的新型长效GLP-1类似物，能激活cAMP信号传导，减少β-抑制蛋白（β-arrestin）介导的内吞和脱敏，从而达到更好血糖控制和体重减轻的效果；信达生物与礼来公司合作开发的GLP-1R/GCGR激动剂玛仕度肽，目前已完成了2项三期临床，据信达估计，其减重和2型糖尿病适应症预计分别将在2025年上半年和下半年获批上市；除此之外，恒瑞医药HRS9531、翰森制药HS-20094、博瑞医药BGM0504等均处在临床三期阶段。 来自口服小分子的挑战 在讨论口服小分子GLP-1R产品之前，我们先看几条重磅新闻： 2023年11月，阿斯利康以1.85亿美金首付款+最高18.25亿美金里程碑付款，获得中国公司诚益生物的一款口服小分子GLP-1R中国以外的所有地区的独家权益 2023年12月，罗氏公司斥巨资31亿美金收购Carmot Therapeutics，其关键资产之一便是口服GLP-1R小分子产品CT-996 2024年5月，恒瑞医药将三款GLP-1R产品HRS-7535（小分子）、HRS-9531（多肽）以及HRS-4729大中华区以外的独家权益打包转让给美国Hercules公司，为此Hercules将向恒瑞医药支付首付款和近期里程碑款1.1亿美金，总交易额超60亿美金。 2024年12月，翰森制药宣布将临床前口服小分子GLP-1受体激动剂HS-10535的全球权益授权给默沙东，为此默沙东需支付1.12亿美金预付款+最高19亿美金里程碑付款，及一定比例的销售分成，协议总金额高达20.12亿美金 毫不夸张的说，一旦口服小分子GLP-1R产品上市，将完全颠覆目前GLP-1R的市场格局。因为与注射相比，口服更加方便，不但可提高患者的用药依从性，而且不存在生物利用度问题，同时口服司美格鲁肽面临的价格昂贵和产能不足的问题也迎刃而解。目前全球领域有两款口服GLP-1R小分子最为引人注意，其中全球进度最快的为礼来公司的Orforglipron，目前已顺利完成二期临床进入三期临床阶段，最早将于2026年初获批上市，其二期临床数据显示，受试组患者体重降幅在8.6%至12.6%之间，而安慰剂组仅为2.0%。36周时，受试组体重降幅达到9.4%至14.7%，达到主要和次要临床终点；另一款产品为歌礼药业的ASC30，既可每月一次皮下注射，也可每日口服一次，同时，其在动物模型中的数据支持更低频率口服给药，或可达一周一次。受此消息影响，歌礼药业盘中大涨，最高涨幅达36%。除此之外，辉瑞、华东医药、硕迪生物、海思科等在此领域也均有布局。 2025年2月5日，诺和诺德发布了2025年16 – 24%的增长预测，相比于2024年的26%略有降低，或许是考虑了全球对司美格鲁肽的实际需求，以及与礼来之间的竞争等因素。但毫无疑问的是，司美格鲁肽注射液在近1-2年仍会是最炙手可热的GLP-1R药物，具体还能大卖几年，就要看上述竞争对手的市场开拓能力与研发速度了。 以上为个人观点，仅供参考 药事纵横投稿须知：稿费已上调，欢迎投稿

As the global pharmaceutical market continues to expand and China's biopharmaceutical industry rapidly advances, in January 2025, several companies announced collaborations with international pharmaceutical giants to launch a series of new drugs globally. From Innovent Biologics' collaboration with Roche on IBI3009 to Lepu Biopharma's licensing agreement with ArriVent for MRG007, these actions highlight the significant role Chinese biopharmaceuticals play in the globalization process. 1.Innovent Biologics joins forces with Roche to make IBI3009 a revolutionary force in treating small cell lung cancer On January 2, 2025, Innovent Biologics announced it had granted Roche the global exclusive rights to the new drug IBI3009. According to the terms of the agreement, Innovent Biologics has transferred to Roche the exclusive global rights to develop, manufacture, and commercialize IBI3009. The parties plan to jointly advance the early developmental stages of this antibody-drug conjugate (ADC), with Roche leading the subsequent clinical development. As part of the deal, Innovent Biologics will receive an upfront payment of $80 million, with the potential to earn up to $1 billion in milestone payments and royalties based on sales. IBI3009 is a next-generation ADC developed by Innovent Biologics, targeting Delta-like ligand 3 (DLL3), a marker that is lowly expressed in normal tissues but highly expressed in specific cancer types such as small cell lung cancer (SCLC). By specifically binding to DLL3, IBI3009 can precisely target cancer cells without harming healthy cells, providing new hope for treatment in advanced SCLC patients. This drug utilizes Innovent Biologics' proprietary new class topoisomerase I inhibitor platform for efficient payload delivery and intracellular toxin release in tumor cells, showing promising antitumor activity and safety. 2.WuXi Biologics partners with Candid Therapeutics to advance a novel trispecific antibody therapy using the WuXiBody™ platform On January 7, 2025, WuXi Biologics entered into a landmark research services collaboration agreement with Candid Therapeutics, marking a new phase in their partnership in the innovation of therapeutic development. Under the agreement, Candid will obtain global rights to a trispecific antibody developed on WuXi Biologics' WuXiBody™ platform, currently in preclinical development, designed to target three different antigen sites: BCMA, CD20, and CD19. BCMA is highly expressed in hematologic malignancies such as multiple myeloma, while CD20 and CD19 are primarily found on the surface of B cells, playing crucial roles in various B-cell-related cancers including non-Hodgkin's lymphoma. This antibody can not only recognize and bind to specific antigens on cancer cells but also activate the patient's immune system, particularly T cells, thereby more effectively clearing tumor cells. WuXi Biologics' WuXiBody™ platform offers unique advantages for this trispecific antibody, enabling simultaneous targeting of tumor cell antigens CD20 and CD19 as well as the T-cell surface activation molecule BCMA, promoting close contact between T cells and tumor cells, enhancing T-cell-mediated cytotoxicity. Furthermore, through this triple targeting mechanism, the antibody may also inhibit the ability of tumor cells to evade immune surveillance, further enhancing therapeutic efficacy. The financial terms of this collaboration are also notable, with WuXi Biologics receiving an undisclosed upfront payment, eligible for subsequent development and sales milestone payments totaling up to $925 million, plus royalties on post-commercialization sales. 3.Duality Biologics Reaches Dual-Specificity ADC Collaboration Agreement with Avenzo Therapeutics On January 8, 2025, Duality Biologics announced an exclusive licensing agreement with Avenzo Therapeutics, granting Avenzo the global rights (excluding Greater China) to develop, manufacture, and commercialize the dual-specificity antibody-drug conjugate (ADC) EGFR/HER3, DB-1418/AVZO-1418. According to the agreement terms, Duality Biologics will receive an upfront payment of $50 million and is eligible for up to $1.15 billion in developmental, regulatory, and commercial milestones, in addition to royalties on sales in Avenzo's designated regions. DB-1418/AVZO-1418 is an innovative dual-specificity ADC that targets EGFR and HER3, which are overexpressed antigens in various cancer types. By targeting both receptors, DB-1418 enhances selective recognition of cancer cells and promotes more effective internalization, delivering its cytotoxic payload – a topoisomerase I inhibitor – directly into the tumor cells to disrupt their DNA replication process, leading to cancer cell death. The ADC leverages Duality Biologics’ proprietary DIBAC platform, ensuring both efficient targeting and stable cargo-carrying capabilities of the antibody, overcoming resistance issues common with traditional single-target therapies. 4.Sciwind Biosciences and Verdiva Bio Seal Major Agreement to Propel Innovation in Metabolic Disease Therapeutics On January 10, 2025, Sciwind Biosciences announced a global development and commercialization license and partnership agreement with Verdiva Bio Limited, focusing on innovative therapies in the cardiovascular metabolic disorder sector. A key product under this collaboration is Ecnoglutide Oral, a potentially first-in-class medication in Phase II clinical trial preparation that requires only once-weekly dosing. As a GLP-1 receptor agonist, Ecnoglutide mimics the action of endogenous GLP-1 by activating the glucagon-like peptide-1 receptor (GLP-1R) which is prevalent in multiple organs including the pancreas, gastrointestinal tract, and heart. Activation of GLP-1R promotes insulin secretion, inhibits glucagon release, and slows gastric emptying, thereby aiding in blood sugar control and weight reduction. Moreover, Ecnoglutide possesses cAMP bias, which may offer unique advantages in activating downstream signaling pathways. Additionally, the partnership agreement includes two amylin receptor agonists, one in oral form and the other as a subcutaneous injection. Amylin, secreted by β-cells alongside insulin, assists in postprandial glucose regulation by delaying gastric emptying, reducing food intake, and lowering postprandial glucose peaks. These amylin receptor agonists are designed to complement the effects of GLP-1 receptor agonists, particularly in terms of weight reduction and improved glucose control. By acting directly on the gastrointestinal tract and through central nervous system mechanisms regulating appetite, co-utilizing amylin with GLP-1 offers a potentially more effective and comprehensive metabolic disease management strategy. This partnership is valued at up to $2.47 billion, including nearly $70 million upfront and up to $2.4 billion in potential development, regulatory, and commercialization milestone payments. Further, Sciwind Biosciences will receive royalties on post-commercialization sales. This substantial financial support not only underscores Verdiva Bio's confidence in the market potential of these candidate drugs but also provides robust financial backing to Sciwind Biosciences to expedite the progress of other projects in its development pipeline. 5. Keymed Biomedical’s CD38 Monoclonal Antibody CM313 On January 10, 2025, Keymed Biomedical announced an exclusive licensing agreement with Timberlyne Therapeutics for the global rights (excluding Mainland China, Hong Kong, Macau, and Taiwan) to CM313, a humanized monoclonal antibody targeting CD38 developed in-house. CM313 is an innovative therapeutic agent that specifically binds to and eliminates tumor cells expressing the CD38 glycoprotein, particularly long-lived plasma cells (LLPCs), thereby preventing antibody-mediated platelet destruction and restoring normal platelet production and function. Additionally, CM313 has the ability to modulate immune cell activity, making it a promising candidate for the treatment of relapsed/refractory multiple myeloma, lymphoma, and other autoimmune diseases. Its mechanism of action extends beyond direct induction of tumor cell apoptosis, also involving indirect tumor cell killing via antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and antibody-dependent cellular phagocytosis (ADCP). Under the terms of the agreement, Keymed Biomedical will receive an upfront and near-term payment of $30 million and will become the largest shareholder of Timberlyne, holding a 25.79% equity stake. Furthermore, upon achieving certain sales and development milestones, Keymed is eligible to receive up to an additional $337.5 million, as well as tiered royalties based on net sales. Notably, Timberlyne has successfully completed a $180 million Series A financing round, attracting investments from prominent institutions such as Bain Capital Life Sciences and Venrock Healthcare Capital Partners. 6. Kelun Botai and Harbour BioMed Partner for Global Expansion of TSLP Monoclonal Antibody SKB378/HBM9378 On January 10, 2025, Kelun Botai and Harbour BioMed jointly announced an exclusive licensing agreement with Windward Bio AG for SKB378/HBM9378, a monoclonal antibody targeting thymic stromal lymphopoietin (TSLP), which they co-developed. SKB378/HBM9378 is a fully human monoclonal antibody designed to inhibit TSLP-mediated signaling by blocking the interaction between TSLP and its receptor, thereby reducing inflammatory responses. The drug has already completed a Phase I clinical trial in China for moderate-to-severe asthma, demonstrating good safety and preliminary efficacy. Under the terms of the agreement, Kelun Botai and Harbour BioMed will receive up to $970 million in upfront and milestone payments from Windward Bio, along with tiered royalties ranging from single-digit to double-digit percentages based on net sales. The upfront and near-term payments total $45 million, consisting of both cash consideration and equity in Windward Bio’s parent company. This collaboration follows a NewCo model, meaning that Windward Bio will assume full responsibility for the global (excluding Greater China and select Southeast and West Asian countries) research, development, manufacturing, and commercialization of SKB378/HBM9378. With further clinical development plans underway, particularly in chronic obstructive pulmonary disease (COPD), SKB378/HBM9378 has the potential to become a novel treatment option for this serious respiratory disease. 7. Simcere Zaiming and AbbVie Join Forces to Advance a New Breakthrough in Multiple Myeloma Treatment On January 13, 2025, Simcere Zaiming entered into a significant development and option licensing agreement with AbbVie, a global pharmaceutical leader. This collaboration focuses on SIM0500, a GPRC5D/BCMA/CD3 trispecific antibody independently developed by Simcere Zaiming. Currently in Phase I clinical trials in both China and the United States, SIM0500 has also been granted Fast Track designation by the U.S. Food and Drug Administration (FDA). As a humanized trispecific antibody targeting multiple myeloma, SIM0500 simultaneously binds to GPRC5D, BCMA, and CD3 on T cells. This multi-target approach enhances tumor cell selectivity and cytotoxicity while improving the safety and efficacy of treatment. Under the terms of the agreement, Simcere Zaiming will receive an upfront payment from AbbVie and is eligible for up to $1.055 billion in option and milestone payments. Additionally, Simcere Zaiming will receive tiered royalties based on net sales of SIM0500 outside Greater China, while AbbVie will be entitled to tiered royalties on net sales within the Greater China region. This agreement not only provides Simcere Zaiming with direct financial benefits but also enables the company to share in the global commercial success of SIM0500. 8. Bispecific Antibody ICP-B02 (CM355): InnoCare Pharma and Keymed Biomedical Collaborate to Pioneer a New Frontier in Tumor Immunotherapy On January 20, 2025, InnoCare Pharma and Keymed Biomedical jointly announced a significant licensing agreement with Prolium Bioscience, granting Prolium the rights to develop and commercialize ICP-B02 (CM355), a bispecific antibody. ICP-B02 is an innovative drug designed to simultaneously recognize and bind to CD20-positive tumor cells and CD3-positive T cells. This dual-targeting mechanism enables ICP-B02 to guide the immune system’s T cells toward tumor cells and activate them to effectively eliminate cancer cells through T cell-dependent cytotoxicity (TDCC). Currently, ICP-B02 is undergoing Phase I/II clinical trials in China, primarily targeting relapsed or refractory non-Hodgkin lymphoma (NHL), including follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Under the terms of the agreement, the two companies will receive payments totaling up to $520 million, including upfront and near-term payments, as well as additional payments upon achieving specified clinical development, regulatory, and commercialization milestones. Additionally, they will retain a minority equity stake in Prolium Bioscience and are entitled to tiered royalties based on future net sales of the product. Prolium has obtained the rights to develop, register, manufacture, and commercialize ICP-B02 in non-oncology indications worldwide and in oncology indications outside Asia. 9. Lepu Biopharma and ArriVent Collaborate to Advance the Globalization of the MRG007 Antibody-Drug Conjugate On January 22, 2025, Lepu Biopharma entered into an exclusive global licensing agreement with ArriVent BioPharma, granting ArriVent the rights to develop, manufacture, and commercialize the innovative antibody-drug conjugate (ADC) MRG007 outside the Greater China region. MRG007 is designed for the treatment of gastrointestinal cancers. Under the agreement, ArriVent gains exclusive rights to MRG007 in all territories outside Mainland China, Hong Kong, Macau, and Taiwan. This collaboration represents a significant milestone for Lepu Biopharma, not only facilitating the advancement of MRG007’s clinical development but also marking an important step in the company’s global expansion strategy. According to the agreement, Lepu Biopharma will receive a total of $47 million in upfront and near-term milestone payments, with additional development, regulatory, and sales milestone payments of up to $1.16 billion. Furthermore, Lepu Biopharma is entitled to tiered royalties based on net sales of MRG007 outside Greater China. This financial arrangement ensures short-term capital inflow for the company while laying a solid foundation for its future success. Moreover, it reflects the international market’s recognition and confidence in MRG007’s potential, signaling that this drug could become a key treatment option for gastrointestinal cancers. Summary January 2025 witnessed a series of significant events in the international expansion of Chinese innovative drugs. These strategic collaborations not only provided substantial financial returns and growth opportunities for Chinese pharmaceutical companies but also expanded global treatment options for patients. For instance, Innovent Biologics accelerated the development of its novel small-cell lung cancer ADC, IBI3009, through a partnership with Roche. Similarly, DualityBio licensed the global rights of its EGFR/HER3 bispecific ADC, DB-1418, to Avenzo Therapeutics, further strengthening its presence in the oncology sector. Additionally, Sciwind Biosciences’ collaboration with Verdiva Bio focused on metabolic diseases, demonstrating the innovative capabilities of Chinese companies beyond oncology. Notably, the financial terms behind these agreements are equally impressive. For example, Keymed Biomedical secured up to $337.5 million in additional payments, while Lepu Biopharma stands to receive up to $1.16 billion in milestone payments. These transactions not only highlight the global market’s high regard for the potential of Chinese innovative drugs but also underscore the strong demand from multinational corporations for high-quality, high-potential pharmaceutical assets when seeking collaboration opportunities. How to get the latest progress on drug deals? If you would like to access the latest transaction event information, you can click on the 'Deal' module from the homepage of the Synapse database. Within the Deal module, you can search for global pharmaceutical transaction information using labels such as Drugs, Organization, Target, Drug Type, Deal Date.  Furthermore, you can obtain the original link to the transaction coverage by clicking on the "Deal Name." In the analysis view, you can see the most active assignors, assignees, popular targets, and other dimensions of analysis, as well as the distribution of research and development statuses at the time of the transaction, to help you better understand the search results. The Synapse database also supports the ability to view current transactions from the dimension of "drugs" (by selecting "drugs" from the "Adjust Dimension" dropdown menu above). Targeting transactions involving renowned pharmaceutical companies that are of interest to the industry, such as Merck, Roche, etc., Synapse has identified a group of "leading companies" through drugs that have achieved global sales exceeding 1 billion US dollars in 2022. Transactions involving drugs from these leading companies can be filtered by clicking on the "Leading Company" tag on the left-hand side. In addition to the drug transaction module, you can also view related transaction history on the drug detail page and the institution detail page. Click on the image below to explore new pharmaceutical funding transactions!